familial mixed hyperlipidemia
Introduction
Introduction to familial mixed hyperlipidemia Familial combined hyperlipidemia (FCH) was an independent disease first recognized in 1973. This type of dyslipidemia is most common in people under 60 years of age with coronary heart disease, and studies have shown that FCH is the most common type of dyslipidemia in patients with ischemic strokes of unknown age over 40 years of age. basic knowledge The proportion of illness: 0.08% Susceptible population: average age is 40 years old Mode of infection: non-infectious Complications: coronary heart disease myocardial infarction ischemic stroke
Cause
The cause of familial mixed hyperlipidemia
Apolipoprotein (Apo) B is produced too much (20%):
Most scholars have found that FCH patients are associated with excessive synthesis of Apo B, and thus the synthesis of VLDL is increased, which may be one of the main pathogenesis of FCH. However, the exact molecular basis for the excessive production of Apo B in FCH patients is not yet available. clear.
Understanding the intracellular processes of Apo B synthesis and secretion may help to clarify the basis for the overproduction of Apo B. Apo B protein has two forms: an Apo B48 (molecular weight 250kD), which is a structural protein of chylomicrons. The other is B100 (molecular weight 512kD), a structural protein of VLDL, IDL and LDL, mainly synthesized by the liver, and the two Apo B are the same gene product.
The regulation mechanism of Apo B secretion has not been fully elucidated. In HepG-2 cells, Apo B is synthesized together with cholesterol in the rough endoplasmic reticulum. The cholesterol-rich neonatal VLDL is transported to the rough endoplasmic reticulum, triacylglycerol. It is also synthesized in the rough endoplasmic reticulum, where triacylglycerol and VLDL are combined into a mature VLDL, which is then secreted by the Golgi. The intracellular Apo B is present in two different functional pools: one in the rough endoplasmic reticulum. On the membrane, it belongs to the degenerative channel; the other is located in the lumen of the endoplasmic reticulum and participates in the synthesis of VLDL. The secretion of Apo B is affected by protein modification. It is believed that Apo B is excessively produced in FCH due to Apo B in hepatocytes. Due to the disorder of the regulation mechanism, the Apo B-containing particles are excessively secreted. In addition, the rate of synthesis of Apo B in the small intestine plays an important role in the pathogenesis of FCH.
However, it is also believed that elevated plasma levels of Apo B may be associated with genetic abnormalities. Apo B gene is known to be polymorphic, and the relationship between Apo B gene polymorphism and elevated plasma Apo B levels is known. The onset of FCH may be helpful. Rauh et al studied three Apo B gene restriction fragment polymorphisms (XbaI, MspI, EcoRI) in FCH patients and normal lipid controls, and the results showed the frequency of these three alleles among subjects. There is no difference, so it is considered that the Apo B mutation is neither the primary cause of FCH nor the change in plasma Apo B levels.
Small particle dense LDL increases (15%):
In addition to the excessive production of Apo B, FCH is characterized by abnormal structural structure of lipoproteins, mainly in LDL, that is, LDL particles contain relatively more Apo B, thus producing small particles dense LDL, the size of such LDL particles. It was negatively correlated with fasting plasma triglyceride concentration and positively correlated with HDL-C level. Sniderman et al. observed the predominance of small particle dense LDL in the plasma of patients with hyperapobeta lipoproteinemia. This condition is often accompanied by significant postprandial hyperlipidemia and delayed granule particle removal. Studies have shown that small particles of dense LDL have a strong atherogenic effect.
Abnormal lipase activity and lipid exchange disorders (15%):
Lipoprotein lipase (LPL) is a key enzyme in lipoprotein metabolism. Its role in the pathogenesis of FCH has gradually been recognized. Under normal conditions, it is rich in triac by LPL. Lipoprotein particles of glycerol such as chylomicrons and triacylglycerols in VLDL are hydrolyzed and produce chylomicron remnants and VLDL remnants, which have a relatively high content of cholesterol and Apo E, and thus Apo E receptors in the liver. The affinity with the LDL receptor is also increased. In this process, the cholesterol in the HDL is exchanged with the triacylglycerol in the triacylglycerol-rich lipoprotein granules, and the exchange process is through cholesterol ester transfer protein (cholesteryl). Ester transfer protein (CETP) works, and it has been confirmed that under normal conditions, LPL is the decisive factor for the clearance of triacylglycerol-rich protein particles in the body. Studies have shown that plasma LPL activity is decreased in 1/3 of patients with FCH. It is suggested that the abnormality of LPL may be related to the pathogenesis of FCH. However, the LPL deficiency alone does not explain the hypertriglyceridemia in all FCH patients. In addition, there are A general survey of gene mutations did not observe a direct link between LPL gene mutations and abnormal plasma lipoprotein phenotypes in FCH patients. Since Apo CII is an activator of LPL, several Apo CII genetic variants are also associated with hyperlipemia. disease.
Most patients with FCH have hypertriglyceridemia, which is generally thought to be due to delayed plasma VLDL clearance. After fat meal, fat in food is transferred to chylomicrons synthesized by the small intestine, which is converted to LPL. The chylomicron residue is removed from the blood circulation by the combination of hepatic lipase (HL), Apo E, residual receptor and LPL, and the VLDL residue also participates in this process of competition, often in FCH patients. The current postprandial hyperlipidemia, this prolonged increase in postprandial lipid levels may be due to the competition between hepatogenic VLDL and intestinal chylomicrons on the same catabolic pathway.
Hypertriglyceridemia in FCH patients is often associated with insulin resistance: fasting hyperinsulinemia, moderate body mass index, systolic hypertension, free fatty acid metabolism disorders, and dyslipidemia.
Abnormal apolipoprotein AI-CIII-AIV gene (10%):
Some studies on 7 families with X2 alleles have found that there is a high correlation between the XmnI marker of Apo AI gene and the hypervariable region of Apo CIII gene and the dyslipidemia phenotype of FCH. In addition, there are reports that The frequency of XmnI and SstI increased in FCH patients, so it is speculated that Apo AI-CIII-AIV gene cluster abnormality may be one of the pathogenic factors of FCH.
Although there have been many studies suggesting that the pathogenesis of FCH is related to certain gene defects, there is no consistent conclusion. It is observed that a variety of genetic abnormalities may be involved in the pathogenesis of FCH, and it is suggested that FCH is a type of inheritance. Not a uniform disease.
Lipolytic disorder in fat cells (8%):
Some studies on catecholamine-promoting lipolysis in 10 patients with FCH and 22 normal subjects have found that the lipolysis induced by catecholamines in fat cells of FCH patients is significantly weakened, and this abnormality is thought to occur in the lipolytic chain reaction. The final step, while directly measuring the activity of hormone sensitive lipase (HSL) in adipose tissue in FCH patients, also showed a 40% reduction.
Prevention
Familial mixed hyperlipidemia prevention
1. At present, there is no specific preventive measure for this disease. It is necessary to strengthen the prevention and treatment personnel's understanding of the disease and understand the harm and serious consequences of the disease.
2. Patients with this disease should take the initiative to receive low-fat and low-carbohydrate diet treatment, and timely use appropriate lipid-lowering drugs to adhere to treatment.
3. Patients should regularly check their blood lipids to maintain normal levels.
4. Actively prevent complications.
Complication
Familial mixed hyperlipidemia complications Complications, coronary heart disease, myocardial infarction, ischemic stroke
There may be complications such as premature coronary heart disease, myocardial infarction, and ischemic stroke.
Symptom
Familial mixed hyperlipidemia symptoms common symptoms dyslipidemia diabetes hypertensive myocardial infarction
1. Male patients with early-onset coronary heart disease are quite common. The average age of coronary heart disease and myocardial infarction is 40 years old. Smoking plays a significant role in promoting its clinical heart disease.
2. Obesity and hypertension are more common in patients with this disease, generally no yellow tumor, even non-specific jaundice can be seen.
3. The dyslipidemia of FCH is characterized by elevated plasma cholesterol and triglyceride, and its biochemical abnormality is similar to type IIb hyperlipoproteinemia.
FCH has been compared with type IIb hyperlipoproteinemia. In addition, many diseases or causes such as diabetes, liver disease, hypothyroidism, kidney disease, malabsorption, obesity, alcoholism or some influencing factors (such as glucocorticoids) , androgen, etc.) may also cause type IIb hyperlipoproteinemia. Therefore, when making a diagnosis of FCH, first of all, it is necessary to exclude secondary hyperlipidemia.
4. The most prominent feature of FCH is that in the same family, various types of patients with hyperlipoproteinemia have been found, and there is a positive family history of patients with myocardial infarction under 60 years of age.
Examine
Examination of familial mixed hyperlipidemia
1. The dyslipidemia of FCH is characterized by elevated plasma cholesterol and triglyceride, and its biochemical abnormality is similar to type IIb hyperlipoproteinemia.
2. Plasma VLDL or LDL increased; plasma Apo B levels increased.
3. Plasma HDL-C and Apo AI decreased slightly.
There is currently no relevant information.
Diagnosis
Diagnosis and identification of familial mixed hyperlipidemia
Diagnostic criteria
The most prominent feature of FCH is that in the same family, various types of patients with hyperlipoproteinemia have been found, and there is a positive family history of myocardial infarction under 60 years of age, due to current metabolic abnormalities and genetic defects in FCH. The gene is still unclear, and no genetic marker with diagnostic significance is found. Therefore, it is necessary to establish a diagnosis of FCH to understand family history. The clinical and biochemical characteristics of FCH and the key points of diagnosis are listed as follows:
1. Among the first generation of relatives, there are many types of patients with high lipoprotein disease.
2. Positive family history of early onset coronary heart disease.
3. Plasma Apo B levels increased.
4. No yellow tumors were detected in the first generation of relatives.
5. There are no hyperlipidemia patients in the family members under the age of 20.
6. Expressed as type IIa, IIb, IV or V hyperlipidemia.
7. LDL-cholesterol/Apo B ratio is reduced.
8. HDL2-cholesterol levels are reduced.
It is generally believed that the presence of points 1, 2 and 3 is sufficient to diagnose the FCH.
Differential diagnosis
Since there is no definitive laboratory method to confirm FCH, the differential diagnosis of FCH is very important. After the exclusion of secondary hyperlipidemia, the differential diagnosis that needs to be considered is: familial hypertriglyceridemia, familial abnormality. --lipoproteinemia and familial hypercholesterolemia.
1. Familial hypertriglyceridemia (FHTG) In FCH, excessive production of VLDL is normal or small particles, while FHTG is a triglyceride-rich VLDL that produces large particles excessively. Simple plasma triglycerides are classified as type IV or V hyperlipidemia. In addition, there is no significant increase in the risk of early onset coronary heart disease among family members.
2. Familial dysbetalipoproteinemia (FD) is characterized by elevated plasma cholesterol and triglyceride levels, mainly due to increased VLDL concentration. Therefore, the identification of FD and FCH is sometimes very difficult. However, patients with FD often have nodular xanthoma or palmo-yellow tumor at the elbow or knee joint, and have characteristic biochemical changes. In addition, Apo E gene mutation is helpful for diagnosing FD.
3. Familial hypercholesterolemia (FH), although mainly manifested as a significant increase in plasma cholesterol concentration, but sometimes accompanied by mild hypertriglyceridemia, manifested as type IIb hyperlipoproteinemia, FH patients often have a variety of yellow tumors, especially in the Achilles tendon, extensor tendon, knee and elbow joints, etc., have diagnostic value, while FCH patients have no yellow tumor, LDL receptor function is normal In addition, FCH patients have a higher age of hyperlipidemia, while those with FH have earlier. FH has been reported to have hypercholesterolemia before the age of 1 year.
